U. IOWA (US) — A misprocessed protein that ends up in the wrong cellular location leads to symptoms of cystic fibrosis, including lung disease and gastrointestinal abnormalities.

The new findings, reported in the journal Science Translational Medicine, match earlier laboratory experiments that suggest gene mutation disrupts the process where the CF protein is folded into its correct shape and shipped to the membranes of cells that line the airways and other organs.

When it is correctly located at the cell membrane, the protein—called cystic fibrosis transmembrane conductance regulator (CFTR)—forms a channel to allow chloride ions to move in and out of cells.

The ion movement is a critical component of the system that maintains salt and water balance across cell membranes in the lungs as well as other organs and supports normal membrane function including eradicating bacteria from cell surfaces.

The CFTR protein behaves the same way in a pig as it does in experimental cell systems, suggesting that they are useful for learning about the CFTR protein’s properties and may also be helpful in testing therapies designed to increase the amount of protein that gets to the cell membrane, or boost the activity of the protein that is located at the membrane.

“Instead of just trying to treat the symptoms of CF, current research is moving toward therapies that target mutations in the CFTR gene,” says David Stoltz, assistant professor of internal medicine at the University of Iowa and senior study author.

“For example, there already are drugs known as “correctors” being tested. These drugs help CFTR move from inside the cell to its correct location on the cell surface.

“The pig model could help us develop and test more corrector drugs, and it will also help us better understand why the protein is misprocessed in the first place,” he adds.

“If we understand what is going wrong, we may be able to develop new therapies that can target the problem and allow more of the CFTR to make it to the cell surface, which may alleviate the disease symptoms.”

In the new pig model, the animals have two copies of the CFTR gene containing the most common CF-causing mutation, which is known as the delta F508 mutation. These pigs also develop CF symptoms similar to the human disease. In particular, the CF pigs are born with gastrointestinal disease and develop lung disease over time.

Most of the CFTR protein is misprocessed and gets degraded—about 6 percent makes it to the cell membrane where it’s able to form active chloride channels—not a sufficient amount to prevent CF disease.

CF is a recessive disease, meaning a person with one mutated copy and one good copy of the CFTR gene is a “carrier” but doesn’t have CF, suggesting that 50 percent of normal CFTR activity is sufficient for health.

The question has always been if a minimal amount of active CFTR would be enough to protect people from disease symptoms.

“We know that people with 50 percent CFTR function have no disease, and now we know that 6 percent of full activity is not enough to prevent disease in the pigs,” Stoltz says. “We still don’t know how much CFTR is enough to prevent the disease, but this model animal could give us a way to investigate.”

Researchers at the University of Missouri contributed to the study, funded in part by the National Institutes of Health and the Cystic Fibrosis Foundation.